Editing MicroRNA (section)

===Heart disease===
The global role of miRNA function in the heart has been addressed by conditionally inhibiting miRNA maturation in the [[Laboratory mouse|murine]] heart. This revealed that miRNAs play an essential role during its development.<ref name="pmid18256189">{{cite journal | vauthors = Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, Rojas M, Hammond SM, Schneider MD, Selzman CH, Meissner G, Patterson C, Hannon GJ, Wang DZ |author-link2=Elizabeth Murchison|author-link13=Gregory Hannon| title = Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 6 | pages = 2111–16 | date = February 2008 | pmid = 18256189 | pmc = 2542870 | doi = 10.1073/pnas.0710228105 | bibcode = 2008PNAS..105.2111C |doi-access=free}}</ref><ref name="2007-Zhao">{{cite journal | vauthors = Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D | title = Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2 | journal = Cell | volume = 129 | issue = 2 | pages = 303–17 | date = April 2007 | pmid = 17397913 | doi = 10.1016/j.cell.2007.03.030 | doi-access = free }}</ref> miRNA expression profiling studies demonstrate that expression levels of specific miRNAs change in diseased human hearts, pointing to their involvement in [[Cardiomyopathy|cardiomyopathies]].<ref name="pmid17606841">{{cite journal | vauthors = Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, Doevendans PA, Mummery CL, Borlak J, Haverich A, Gross C, Engelhardt S, Ertl G, Bauersachs J | title = MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure | journal = Circulation | volume = 116 | issue = 3 | pages = 258–67 | date = July 2007 | pmid = 17606841 | doi = 10.1161/CIRCULATIONAHA.107.687947 | doi-access = free }}</ref><ref name="pmid17108080">{{cite journal | vauthors = van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson JA, Olson EN | title = A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 48 | pages = 18255–60 | date = November 2006 | pmid = 17108080 | pmc = 1838739 | doi = 10.1073/pnas.0608791103 | bibcode = 2006PNAS..10318255V | doi-access = free }}</ref><ref name="pmid17498736">{{cite journal | vauthors = Tatsuguchi M, Seok HY, Callis TE, Thomson JM, Chen JF, Newman M, Rojas M, Hammond SM, Wang DZ | title = Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy | journal = Journal of Molecular and Cellular Cardiology | volume = 42 | issue = 6 | pages = 1137–41 | date = June 2007 | pmid = 17498736 | pmc = 1934409 | doi = 10.1016/j.yjmcc.2007.04.004 }}</ref> Furthermore, animal studies on specific miRNAs identified distinct roles for miRNAs both during heart development and under pathological conditions, including the regulation of key factors important for cardiogenesis, the hypertrophic growth response and cardiac conductance.<ref name="2007-Zhao"/><ref>{{cite journal | vauthors = Zhao Y, Samal E, Srivastava D | title = Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis | journal = Nature | volume = 436 | issue = 7048 | pages = 214–20 | date = July 2005 | pmid = 15951802 | doi = 10.1038/nature03817 | bibcode = 2005Natur.436..214Z | s2cid = 4340449 }}</ref><ref name="pmid17401374">{{cite journal | vauthors = Yang B, Lin H, Xiao J, Lu Y, Luo X, Li B, Zhang Y, Xu C, Bai Y, Wang H, Chen G, Wang Z | title = The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 | journal = Nature Medicine | volume = 13 | issue = 4 | pages = 486–91 | date = April 2007 | pmid = 17401374 | doi = 10.1038/nm1569 | s2cid = 1935811 }}</ref><ref name="pmid17468766">{{cite journal | vauthors = Carè A, Catalucci D, Felicetti F, Bonci D, Addario A, Gallo P, Bang ML, Segnalini P, Gu Y, Dalton ND, Elia L, Latronico MV, Høydal M, Autore C, Russo MA, Dorn GW, Ellingsen O, Ruiz-Lozano P, Peterson KL, Croce CM, Peschle C, Condorelli G | title = MicroRNA-133 controls cardiac hypertrophy | journal = Nature Medicine | volume = 13 | issue = 5 | pages = 613–18 | date = May 2007 | pmid = 17468766 | doi = 10.1038/nm1582 | s2cid = 10097893 }}</ref><ref name="pmid17379774">{{cite journal | vauthors = van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN | title = Control of stress-dependent cardiac growth and gene expression by a microRNA | journal = Science | volume = 316 | issue = 5824 | pages = 575–79 | date = April 2007 | pmid = 17379774 | doi = 10.1126/science.1139089 | bibcode = 2007Sci...316..575V | s2cid = 1927839 }}</ref> Another role for miRNA in cardiovascular diseases is to use their expression levels for diagnosis, prognosis or risk stratification.<ref>{{cite journal | vauthors = Keller T, Boeckel JN, Groß S, Klotsche J, Palapies L, Leistner D, Pieper L, Stalla GK, Lehnert H, Silber S, Pittrow D, Maerz W, Dörr M, Wittchen HU, Baumeister SE, Völker U, Felix SB, Dimmeler S, Zeiher AM | title = Improved risk stratification in prevention by use of a panel of selected circulating microRNAs | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 4511 | date = July 2017 | pmid = 28674420 | pmc = 5495799 | doi = 10.1038/s41598-017-04040-w | bibcode = 2017NatSR...7.4511K }}</ref> miRNA's in animal models have also been linked to cholesterol metabolism and regulation.

====miRNA-712====
[[Murine]] microRNA-712 is a potential biomarker (i.e. predictor) for [[atherosclerosis]], a cardiovascular disease of the arterial wall associated with lipid retention and inflammation.<ref>{{cite journal | vauthors = Insull W | title = The pathology of atherosclerosis: plaque development and plaque responses to medical treatment | journal = The American Journal of Medicine | volume = 122 | issue = 1 Suppl | pages = S3–S14 | date = January 2009 | pmid = 19110086 | doi = 10.1016/j.amjmed.2008.10.013 }}</ref> Non-laminar blood flow also correlates with development of atherosclerosis as mechanosenors of endothelial cells respond to the shear force of disturbed flow (d-flow).<ref name="Son_2013">{{cite journal | vauthors = Son DJ, Kumar S, Takabe W, Kim CW, Ni CW, Alberts-Grill N, Jang IH, Kim S, Kim W, Won Kang S, Baker AH, Woong Seo J, Ferrara KW, Jo H | title = The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis | journal = Nature Communications | volume = 4 | pages = 3000 | year = 2013 | pmid = 24346612 | pmc = 3923891 | doi = 10.1038/ncomms4000 | bibcode = 2013NatCo...4.3000S }}</ref> A number of pro-atherogenic genes including [[matrix metalloproteinase]]s (MMPs) are upregulated by d-flow,<ref name="Son_2013" /> mediating pro-inflammatory and pro-angiogenic signals. These findings were observed in ligated carotid arteries of mice to mimic the effects of d-flow. Within 24 hours, pre-existing immature miR-712 formed mature miR-712 suggesting that miR-712 is flow-sensitive.<ref name="Son_2013" /> Coinciding with these results, miR-712 is also upregulated in endothelial cells exposed to&nbsp;naturally occurring d-flow&nbsp;in the greater curvature of the aortic arch.<ref name="Son_2013" />

====Origin====
Pre-mRNA sequence of miR-712 is generated from the murine ribosomal RN45s gene at the [[internal transcribed spacer]] region 2 (ITS2).<ref name="Son_2013" /> XRN1 is an exonuclease that degrades the ITS2 region during processing of RN45s.<ref name="Son_2013" /> Reduction of XRN1 under d-flow'' ''conditions therefore leads to the accumulation of miR-712.<ref name="Son_2013" />

====Mechanism====
MiR-712 targets tissue inhibitor of [[Metalloproteinase|metalloproteinases 3]] (TIMP3).<ref name="Son_2013" /> TIMPs normally regulate activity of matrix metalloproteinases (MMPs) which degrade the extracellular matrix (ECM). Arterial ECM is mainly composed of [[collagen]] and [[elastin]] fibers, providing the structural support and recoil properties of arteries.<ref name=":1">{{cite journal | vauthors = Basu R, Fan D, Kandalam V, Lee J, Das SK, Wang X, Baldwin TA, Oudit GY, Kassiri Z | title = Loss of Timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin II | journal = The Journal of Biological Chemistry | volume = 287 | issue = 53 | pages = 44083–96 | date = December 2012 | pmid = 23144462 | pmc = 3531724 | doi = 10.1074/jbc.M112.425652 | doi-access = free }}</ref> These fibers play a critical role in regulation of vascular inflammation and permeability, which are important in the development of atherosclerosis.<ref>{{cite journal | vauthors = Libby P | title = Inflammation in atherosclerosis | journal = Nature | volume = 420 | issue = 6917 | pages = 868–74 | year = 2002 | pmid = 12490960 | doi = 10.1038/nature01323 | bibcode = 2002Natur.420..868L | s2cid = 407449 }}</ref> Expressed by endothelial cells, TIMP3 is the only ECM-bound TIMP.<ref name=":1" /> A decrease in TIMP3 expression results in an increase of ECM degradation in the presence of d-flow. Consistent with these findings, inhibition of pre-miR712 increases expression of TIMP3 in cells, even when exposed to turbulent flow.<ref name="Son_2013" />

TIMP3 also decreases the expression of TNFα (a pro-inflammatory regulator) during turbulent flow.<ref name="Son_2013" /> Activity of TNFα in turbulent flow was measured by the expression of TNFα-converting enzyme (TACE) in blood. TNFα decreased if miR-712 was inhibited or TIMP3 overexpressed,<ref name="Son_2013" /> suggesting that miR-712 and TIMP3 regulate TACE activity in turbulent flow conditions.

Anti-miR-712 effectively suppresses d-flow-induced miR-712 expression and increases TIMP3 expression.<ref name="Son_2013" /> Anti-miR-712 also inhibits vascular hyperpermeability, thereby significantly reducing atherosclerosis lesion development and immune cell infiltration.<ref name="Son_2013" />

====Human homolog microRNA-205====

The human homolog of miR-712 was found on the RN45s homolog gene, which maintains similar miRNAs to mice.<ref name="Son_2013" /> MiR-205 of humans share similar sequences with miR-712 of mice and is conserved across most vertebrates.<ref name="Son_2013" /> MiR-205 and miR-712 also share more than 50% of the cell signaling targets, including TIMP3.<ref name="Son_2013" />

When tested, d-flow decreased the expression of XRN1 in humans as it did in mice endothelial cells, indicating a potentially common role of XRN1 in humans.<ref name="Son_2013" />